PURPOSE OF REVIEW: In this review, we discuss the causes for a failed weaning trial and specific diagnostic tests that could be conducted to identify the cause for weaning failure. We briefly highlight treatment strategies that may enhance the chance of weaning success. RECENT FINDINGS: Impaired respiratory mechanics, respiratory muscle dysfunction, cardiac dysfunction, cognitive dysfunction, and metabolic disorders are recognized causes for weaning failure. In addition, iatrogenic factors may be at play. Most studies have focused on respiratory muscle dysfunction and cardiac dysfunction. Recent studies demonstrate that both ultrasound and electromyography are valuable tools to evaluate respiratory muscle function in ventilated patients. Sophisticated ultrasound techniques and biomarkers such as B-type natriuretic peptide, are valuable tools to identify cardiac dysfunction as a cause for weaning failure. Once a cause for weaning failure has been identified specific treatment should be instituted. Concerning treatment, both strength training and endurance training should be considered for patients with respiratory muscle weakness. Inotropes and vasodilators should be considered in case of heart failure. SUMMARY: Understanding the complex pathophysiology of weaning failure in combination with a systematic diagnostic approach allows identification of the primary cause of weaning failure. This will help the clinician to choose a specific treatment strategy and therefore may fasten liberation from mechanical ventilation.